A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

Shan Wang; Sixing Lin; Qing Fang; Roland Gyampoh; Zhou Lu; Yingli Gao; David J Clarke; Kewen Wu; Laurent Trembleau; Yi Yu; Kwaku Kyeremeh; Bruce F Milne; Jioji Tabudravu; Hai Deng

doi:10.1038/s41467-022-32774-3

A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

Shan Wang, Sixing Lin, Qing Fang, Roland Gyampoh, Zhou Lu, Yingli Gao, David J Clarke, Kewen Wu, Laurent Trembleau, Yi Yu^* (Corresponding Author), Kwaku Kyeremeh^* (Corresponding Author), Bruce F Milne^* (Corresponding Author), Jioji Tabudravu^* (Corresponding Author), Hai Deng^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

1 Downloads (Pure)

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.

Original language	English
Article number	5044
Number of pages	15
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	26 Aug 2022
DOIs	https://doi.org/10.1038/s41467-022-32774-3
Publication status	Published - 26 Aug 2022

Bibliographical note

Acknowledgements
This work received financial support from Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, D.J.C., BB/R013993/1), Scottish Funding Council Covid-19 Grant extension and Bridging Fund (S.W. and H.D.); UKRI Covid-19 Extension Allocation Fund (S.W. and H.D.); The Elphinstone Scholarship of University of Aberdeen (QF), Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1 to K.K. and H.D.), and National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y., 31929001 to H.D.), and the Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617 to H.D. and Y.Y.). B.F.M. thanks the Portuguese Foundation for Science and Technology for financial support (POCI-01-0145-FEDER-032229 and CENTRO-01-0145-FEDER-000014, 2017-2020). H.D. and S.W. thank Professor Brady Moore in the Scripps Institute of Oceanography, University of San Diego, USA, for the gift of pCAP003 plasmid, Dr. Vladimir Larionov in National Cancer Institute, National Institute of Health, Bethesda, USA for the gift of Sacharomyces cerevisiae VL6-48N strain, Dr Juan-Pablo Gomez-Escribano and Professor Mervyn Bibb in John Innes Centre, UK for the gift of Streptomyces coelicolor M1152, and Samantha Law and Carol Philips in NCIMB Ltd (UK) for the kind gift of Streptomyces kurssanovii NCIMB12788

Keywords

Biochemistry
Biosynthesis
Natural products
Peptides

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-022-32774-3Licence: CC BY

Wang_etal_NC_A_Ribosomally_Synthetised_VoR
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 2.42 MBLicence: CC BY

Marine Biodiscovery Centre
Marcel Jaspars (Manager)
The Marine Biodiscovery Centre
Research Facilities: Facility

Cite this

Wang, S., Lin, S., Fang, Q., Gyampoh, R., Lu, Z., Gao, Y., Clarke, D. J., Wu, K., Trembleau, L., Yu, Y., Kyeremeh, K., Milne, B. F., Tabudravu, J., & Deng, H. (2022). A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif. Nature Communications, 13(1), Article 5044. https://doi.org/10.1038/s41467-022-32774-3

@article{20fcc50d72ef4a1e8661c5d400cc6c6c,

title = "A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif",

abstract = "Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.",

keywords = "Biochemistry, Biosynthesis, Natural products, Peptides",

author = "Shan Wang and Sixing Lin and Qing Fang and Roland Gyampoh and Zhou Lu and Yingli Gao and Clarke, {David J} and Kewen Wu and Laurent Trembleau and Yi Yu and Kwaku Kyeremeh and Milne, {Bruce F} and Jioji Tabudravu and Hai Deng",

note = "Acknowledgements This work received financial support from Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, D.J.C., BB/R013993/1), Scottish Funding Council Covid-19 Grant extension and Bridging Fund (S.W. and H.D.); UKRI Covid-19 Extension Allocation Fund (S.W. and H.D.); The Elphinstone Scholarship of University of Aberdeen (QF), Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1 to K.K. and H.D.), and National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y., 31929001 to H.D.), and the Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617 to H.D. and Y.Y.). B.F.M. thanks the Portuguese Foundation for Science and Technology for financial support (POCI-01-0145-FEDER-032229 and CENTRO-01-0145-FEDER-000014, 2017-2020). H.D. and S.W. thank Professor Brady Moore in the Scripps Institute of Oceanography, University of San Diego, USA, for the gift of pCAP003 plasmid, Dr. Vladimir Larionov in National Cancer Institute, National Institute of Health, Bethesda, USA for the gift of Sacharomyces cerevisiae VL6-48N strain, Dr Juan-Pablo Gomez-Escribano and Professor Mervyn Bibb in John Innes Centre, UK for the gift of Streptomyces coelicolor M1152, and Samantha Law and Carol Philips in NCIMB Ltd (UK) for the kind gift of Streptomyces kurssanovii NCIMB12788",

year = "2022",

month = aug,

day = "26",

doi = "10.1038/s41467-022-32774-3",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

AU - Wang, Shan

AU - Lin, Sixing

AU - Fang, Qing

AU - Gyampoh, Roland

AU - Lu, Zhou

AU - Gao, Yingli

AU - Clarke, David J

AU - Wu, Kewen

AU - Trembleau, Laurent

AU - Yu, Yi

AU - Kyeremeh, Kwaku

AU - Milne, Bruce F

AU - Tabudravu, Jioji

AU - Deng, Hai

N1 - Acknowledgements This work received financial support from Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, D.J.C., BB/R013993/1), Scottish Funding Council Covid-19 Grant extension and Bridging Fund (S.W. and H.D.); UKRI Covid-19 Extension Allocation Fund (S.W. and H.D.); The Elphinstone Scholarship of University of Aberdeen (QF), Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1 to K.K. and H.D.), and National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y., 31929001 to H.D.), and the Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617 to H.D. and Y.Y.). B.F.M. thanks the Portuguese Foundation for Science and Technology for financial support (POCI-01-0145-FEDER-032229 and CENTRO-01-0145-FEDER-000014, 2017-2020). H.D. and S.W. thank Professor Brady Moore in the Scripps Institute of Oceanography, University of San Diego, USA, for the gift of pCAP003 plasmid, Dr. Vladimir Larionov in National Cancer Institute, National Institute of Health, Bethesda, USA for the gift of Sacharomyces cerevisiae VL6-48N strain, Dr Juan-Pablo Gomez-Escribano and Professor Mervyn Bibb in John Innes Centre, UK for the gift of Streptomyces coelicolor M1152, and Samantha Law and Carol Philips in NCIMB Ltd (UK) for the kind gift of Streptomyces kurssanovii NCIMB12788

PY - 2022/8/26

Y1 - 2022/8/26

N2 - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.

AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.

KW - Biochemistry

KW - Biosynthesis

KW - Natural products

KW - Peptides

U2 - 10.1038/s41467-022-32774-3

DO - 10.1038/s41467-022-32774-3

M3 - Article

C2 - 36028509

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5044

ER -

A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Fingerprint

Equipment

Marine Biodiscovery Centre

Cite this